|Structural Biochemistry - CNRS URA2185|
|HEAD||ALZARI Pedro / firstname.lastname@example.org|
|MEMBERS||Dr ALBANESI Daniela / Dr ANDRE-LEROUX Gwénaëlle / Dr BELLINZONI Marco
Dr BETTON Jean-Michel / Dr ENGLAND Patrick / GRANA Martin / Dr GUERIN Marcelo
HINDIE Valérie / MIOT Marie-Caroline / Dr OPPEZZO Pablo / Dr PECORARI Fréderic
Dr SCHAEFFER Francis / TELLO Diana / WEHENKEL Anne-Marie
Our research activities are oriented towards the biochemical, biophysical and structural studies of proteins involved in microbial pathogenesis. Some ongoing projects are described below; additional information can be found in our Web page: http://www.pasteur.fr/recherche/unites/Bstruct.
Mycobacterial Ser/Thr protein kinases and phosphatases. Bacterial signaling involves primarily the action of two-component systems. However, M. tuberculosis includes several genes coding for Ser/Thr protein kinases (11) and phosphatases (3). As part of our systematic structural and biochemical studies of these eukaryotic-like TB proteins, we have determined the 3D structures of PstP and PknB, a cognate phosphatase-kinase pair involved in cell growth control and we are currently working to identify their physiological substrates. We showed that the pknB gene is essential for TB growth and that PknB inhibitors have anti-mycobacterial activity. Our efforts are now focused on the elucidation of the signalling pathway(s) and the development of specific inhibitors of PknB and other TB targets, as part of the European Project NM4TB.
Global regulation of lipid biosynthesis in bacteria. We showed that malonyl-CoA is the specific effector of FapR, a transcriptional repressor that controls the expression of several genes involved in fatty acid synthesis in several Gram+ bacteria. The 3D structure of B. subtilis FapR revealed a thioesterase-like homodimer, where ligand binding induces a disorder-to-order transition that disrupts DNA-binding (Fig. 1). Structure-based mutants that impair malonyl-CoA binding also abolish regulation in vivo and result in a lethal (super-repressor) phenotype. Our current studies are focused on FapR from human pathogens such as Staphylococcus aureus and Listeria monocytogenes, to validate this homeostatic pathway as a potential therapeutic target.
Protein folding and secretion mechanisms in bacteria (J.M. Betton) Our group studies bacterial quality control systems for the development of more efficient protein expression processes. Proteins aggregate when E. coli cells are exposed to environmental stress or when they overexpress recombinant genes (protein factories). In these cases, proteins may fail to fold sufficiently rapidly or remain correctly folded, and form aggregates if they escape the cellular quality-control systems. The CpxA/R signal transduction system senses perturbations in the periplasm and responds by up-regulating several protein folding and degrading activities. For these studies we use cell-free expression systems to express membrane proteins in the presence of detergent micelles. Current projects include the function of the periplasmic protease DegP/HtrA, and biochemical and structural analysis of proteins involved in the CpxA/R system.
|More informations on our web site|
|Publications 2006 of the unit on Pasteur's references database|
Activity Reports 2006 - Institut Pasteur
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